Widening the clinical window for diagnosing fetal-onset hypogonadism in boys, "Beyond the Abstract," by Rodolfo Rey, MD, PhD

BERKELEY, CA (UroToday.com) - Congenital male hypogonadism can be primary (usually called hypergonadotropic, the testis is primarily affected) or central (usually called hypogonadotropic, the hypothalamic-gonadotrope axis is primarily affected). On the other hand, hypogonadism, whether primary or central, may be established already in the first trimester of fetal development, or later on. The clinical presentation differs according to whether it is primary/central and early/late fetal onset.

The reason for these different clinical presentations lies on the ontogeny and physiology of the hypothalamic-pituitary-testicular axis: in early fetal development, the testis secretes – independent of pituitary gonadotropins – androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. Therefore, in the first trimester, only primary hypogonadism is possible and results in deficient virilization of the XY fetus. According to the extent of the defect, the newborn may depict a completely feminized anatomic phenotype or ambiguous genitalia. If the disorder is established during the second half of fetal life, the anatomic phenotype is male but the penis and testes are usually smaller (micropenis and micro-orchidism), and the gonads do not descend to scrotal position (cryptorchidism). The condition may be due to either a primary testicular defect (mild testicular dysgenesis, vanishing testes, etc.) or to a central defect in gonadotropin production (isolated hypogonadotropic hypogonadism or multiple pituitary hormone deficiency, also known as panhypopituitarism). The latter may include ACTH deficiency resulting in life-threatening adrenal failure, GH deficiency leading to severe hypoglycemia, and TSH deficiency resulting in hypothyroidism which affects early brain development. Therefore, the presence of micropenis and micro-orchidism or cryptorchidism should prompt pituitary-gonadal assessment by measuring gonadotropins LH and FSH, as well as testicular hormones AMH and inhibin B (Sertoli cell markers) and testosterone and INSL3 (Leydig cell markers) during the first 6 months after birth. If all hormone levels are low, central hypogonadism is suspected, and other pituitary axes should be examined (ACTH, GH, TSH). Beyond the age of 6 months, gonadotropins, testosterone and INSL3 decline normally, and are no longer informative. However, Sertoli cell markers AMH and inhibin B remain useful markers to assess gonadal function and diagnose hypogonadism during the rest of infancy and childhood.

Written by:
Rodolfo Rey, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Director, Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE)
CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez
Gallo 1330 – C1425EFD Buenos Aires

Spreading the clinical window for diagnosing fetal-onset hypogonadism in boys - Abstract

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